title: Epstein-Barr virus nuclear antigen-1 renders lymphocytes responsive to IL-2 but not IL-15 for survival.
abstract: Epstein-Barr virus nuclear antigen-1 (EBNA-1) is the only latent protein expressed in all virus-associated tumours. It plays a critical role in viral propagation and in the replication, episomal maintenance and partitioning of the viral genome. However, its tumorigenic potential is debated. We have previously shown that lymphocytes from a tumour-prone, EBNA-1-expressing, transgenic mouse line show increased responsiveness to interleukin-2 (IL-2). It was important to determine whether this property was unique to the transgenic line or whether it is a general consequence of EBNA-1 expression in B cells. In order to distinguish between these possibilities, explanted lymphocytes from two independent transgenic mouse lines were examined. The lymphocytes from both lines showed enhanced proliferation rates compared with controls. The transgenic lymphocytes survived for extended periods in culture, dependent on the dose of IL-2, while IL-15 (the receptor of which shares the beta and gamma chain components of the IL-2 receptor) induced little effect. In accordance with this, transgenic B cells showed enhanced induction of expression of the IL-2 receptor alpha chain (CD25), which modulates affinity for the ligand. As this phenotype is evident in lymphocytes from mice of both lines, it is necessarily independent of any transgene insertion site effects and may be attributed to EBNA-1 expression. Furthermore, 10/12 tumour-bearing transgenic mice had elevated IL-2 levels in serum and 4/6 tumours were CD25 positive. IL-2 is normally produced by activated T cells in vivo; thus, chronic immune activation or modulation could elicit this unique mode of virus-infected cell survival.
authors.affiliation: Division of Molecular and Cellular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, UK.
authors.forename: Penelope
authors.initials: P
authors.lastname: Tsimbouri
authors.affiliation: Division of Molecular and Cellular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, UK.
authors.forename: Yazeed
authors.initials: Y
authors.lastname: Al-Sheikh
authors.affiliation: Division of Molecular and Cellular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Drotar
authors.affiliation: Division of Molecular and Cellular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, UK.
authors.forename: William
authors.initials: W
authors.lastname: Cushley
authors.affiliation: Division of Molecular and Cellular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, UK.
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Wilson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D019309:Epstein-Barr Virus Nuclear Antigens / Q000502:physiology*; D005434:Flow Cytometry; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D019409:Interleukin-15 / Q000096:biosynthesis / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology*; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D008223:Lymphoma / Q000473:pathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D013936:Thymidine / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D019309:Epstein-Barr Virus Nuclear Antigens; D019409:Interleukin-15; D007376:Interleukin-2; C417029:EBV-encoded nuclear antigen 1; D013936:Thymidine